Faculty, Staff and Student Publications
Publication Date
5-21-2024
Journal
Circulation
Abstract
Background: Much of our knowledge of organ rejection after transplantation is derived from rodent models.
Methods: We used single-nucleus RNA sequencing to investigate the inflammatory myocardial microenvironment in human pediatric cardiac allografts at different stages after transplantation. We distinguished donor- from recipient-derived cells using naturally occurring genetic variants embedded in single-nucleus RNA sequencing data.
Results: Donor-derived tissue resident macrophages, which accompany the allograft into the recipient, are lost over time after transplantation. In contrast, monocyte-derived macrophages from the recipient populate the heart within days after transplantation and form 2 macrophage populations: recipient MP1 and recipient MP2. Recipient MP2s have cell signatures similar to donor-derived resident macrophages; however, they lack signatures of pro-reparative phagocytic activity typical of donor-derived resident macrophages and instead express profibrotic genes. In contrast, recipient MP1s express genes consistent with hallmarks of cellular rejection. Our data suggest that recipient MP1s activate a subset of natural killer cells, turning them into a cytotoxic cell population through feed-forward signaling between recipient MP1s and natural killer cells.
Conclusions: Our findings reveal an imbalance of donor-derived and recipient-derived macrophages in the pediatric cardiac allograft that contributes to allograft failure.
Keywords
Humans, Heart Transplantation, Macrophages, Allografts, Graft Rejection, Male, Female, Child, Child, Preschool, Myocardium, Graft Survival, Infant, Killer Cells, Natural, Adolescent, Cardiac, Allograft, Donor, Recipient, Macrophage, NK cells, pediatrics
DOI
10.1161/CIRCULATIONAHA.123.065294
PMID
38344825
PMCID
PMC11105989
PubMedCentral® Posted Date
5-21-2025
PubMedCentral® Full Text Version
Post-print
Recommended Citation
Li, Xiao; Turaga, Diwakar; Li, Rich G; Tsai, Chang-Ru; Quinn, Julianna N; Zhao, Yi; Wilson, Ruby; Carlson, Katherine; Wang, Jun; Spinner, Joseph A; Hickey, Edward J; Adachi, Iki; and Martin, James F, "The Macrophage Landscape Across the Lifespan of a Human Cardiac Allograft" (2024). Faculty, Staff and Student Publications. 101.
https://digitalcommons.library.tmc.edu/uthdb_docs/101
Published Open-Access
yes